Human interleukin-6 (IL6), a secreted glycoprotein having 184 amino acids (21 kDa), has a four-helix bundle structure. IL6 is a multi-functional cytokine that acts on various type of cells, e.g., B cells, T cells, fibroblasts, hepatocytes, osteoclasts, neural cells, mesangial cells, epidermal keratinocytes, and hematopoietic progenitor cells, via binding to two distinct receptor proteins, the IL6 receptor (IL6R) and glycoprotein 130 (gp130). Formation of the IL6/IL6R/gp130 complex transduces intracellular signaling pathways, including those mediated by (1) phosphatidyl inositol-3′-kinase (PI3K), (2) mitogen-activated protein kinase (MAK), and (3) Janus tyrosine kinase (JAK)-signal transducer and activator of transcription 1 and 3 (STAT1 and STAT3).
IL6 functions as an immune regulator, cell growth factor, bone metabolism regulator, cell differentiation factor, and acute phase protein inducer against several effecter cells. In liver, IL6 induces various acute-phase proteins such as serum amyloid A (SAA), C-reactive protein (CRP), hepcidin, fibrinogen, and haptoglobin antichymotrypsin. The pathological significance of IL6 for various diseases has been indicated in numerous studies, including chronic inflammatory diseases, autoimmune diseases (e.g., rheumatoid arthritis, Crohn's disease, Castleman's disease and psoriasis), cancer (e.g., multiple myeloma, leukemia, breast cancer, pancreatic cancer, prostate cancer and various cancers), and cachexia and coronary heart disease.
It is therefore of great interest to develop new IL6 antagonists for use in treating diseases associated with the IL6 signaling.